1. Field of the Invention
The present invention relates to pharmaceutical compositions useful for parenteral administration of taxoid drugs or other insoluble drugs. More specifically, the present invention relates to injectable oil-in-water emulsions of taxoid drugs or other water insoluble drugs characterized as being low in oil content, small in droplet size, being stable, and being ready-to-use.
2. Description of the Related Art
Taxoid drugs are widely used in cancer chemotherapy. Because they tend to be highly toxic, taxoid drugs are almost always administered via injection or infusion of liquid solutions to better control their blood-borne concentrations. However, due to very high levels of insolubility of taxoid drugs, intravenous injection or infusion of these drugs poses serious problems and challenges for pharmaceutical scientists and physicians as well as serious side effects to the patient. Various methods for emulsifying, suspending, or encapsuling insoluble drugs in injectable formulations have been used for decades, but none of those approaches are fully satisfactory for taxoid drugs, and the “best available” formulations of paclitaxel and docetaxel drugs pose serious problems, risks, and drawbacks. Such problems include, for example, high rates of allergic and/or immune reactions, severe pain at injection sites, serious and potentially permanent damage to blood vessels at or near the site of injection.
Among all side effects, the allergic and/or immune reactions are the most serious and sometimes of fatal risk, and for that reason, the FDA has requested the manufacturers of paclitaxel and docetaxel to include a “black box” warning label for these products. For example, the “black box” warning for paclitaxel (TAXOL™) reads as follows:
“Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving TAXOL™ in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists.”
The “black box” warning for docetaxel (TAXOTERE™) states:
“Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or generalized rash/erythema occurred in 2.2% ( 2/92) of patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of the TAXOTERE™ infusion were reported in five patients who did not receive premedication. These reactions resolved after discontinuation of the infusion and the administration of appropriate therapy. TAXOTERE™ must not be given to patients who have a history of severe hypersensitivity reactions to TAXOTERE™ or to other drugs formulated with polysorbate 80.”
However, the severe adverse reactions of these two important drugs are not due to the drugs themselves, but to the inactive ingredients used in their formulations. For TAXOL™, the anaphylaxis and severe hypersensitivity are caused by Cremophor® EL (polyoxyethylated castor oil), and for TAXOTERE™, polysorbate 80.
It is therefore apparent that there exist serious limitations and shortcomings in the current state of the art for injecting insoluble taxoid drugs as well as for injecting other types of highly insoluble drugs.